Natural products as kinase inhibitors in lung cancer: molecular mechanisms, therapeutic potential, and clinical trials

Lung cancer remains a leading cause of cancer mortality worldwide, with current treatments often limited by toxicity and resistance. Dysregulated kinase signaling particularly involving EGFR, PI3K/AKT/mTOR, MAPK, and ALK pathways drives tumor growth, survival, and metastasis. While synthetic kinase inhibitors have improved outcomes, their use is constrained by adverse effects and acquired resistance. Natural kinase inhibitors (NKIs) derived from plants, marine organisms, and microorganisms offer a promising alternative due to their multi-targeted action, lower toxicity, and potential to overcome resistance. This review aims to evaluate the molecular mechanisms, therapeutic potential, and clinical relevance of NKIs in lung cancer management. Key compounds such as curcumin, resveratrol, quercetin, genistein, and epigallocatechin gallate inhibit critical kinases, modulating pathways that regulate proliferation, apoptosis, angiogenesis, and metastasis. Preclinical studies demonstrate significant anticancer activity, while emerging clinical evidence supports their role as adjuncts or alternatives to conventional therapies. Strategies such as nanotechnology-based delivery systems and combination regimens further enhance bioavailability and efficacy. Despite these advantages, challenges persist, including poor solubility, rapid metabolism, and limited clinical validation. Future research should focus on optimizing formulations, elucidating pharmacokinetics, and conducting large-scale clinical trials to confirm safety and effectiveness. Integration of NKIs into personalized treatment paradigms could transform lung cancer therapy, offering cost-effective, less toxic, and multi-targeted approaches to improve patient outcomes.